Other derivatives of folic acid and aminopterin have been synthesized and tested as antimetabolites. Among these are compounds in which a methylene or methylidene group occupies a position in the molecule normally occupied by an imino or nitrilo group, respectively. These derivatives have varying degrees of antimetabolic activity. 10-Deazaaminopterin is highly active (Sirotnak et al., Cancer Treat. Rep., 62: 1047 (1978)) and 5-deazaaminopterin has activity similar to that of amethopterin (Taylor et al., J. Org. Chem., 48: 4842 (1983)). 8,10-Dideazaaminopterin is reported to be antimetabolically active (U.S. Pat. No. 4,460,591) and 5,8,10-trideazaaminopterin exhibits activity against mouse L1210 leukemia (Yan et al., J. Heterocycl. Chem., 16:541 (1979)). 10-Deazafolic acid, on the other hand, shows no significant activity (Struck et al., J. Med. Chem., 14:693 (1971)) and 5-deazafolic acid is only weakly cytotoxic. 8,10-Dideazafolic acid is only marginally effective as a dihydrofolate reductase inhibitor (De Graw et al., "Chemistry and Biology of Pteridines", Elsevier, 229 (1979)) and 5,8,10-trideazafolic acid also shows only marginal activity against mouse L1210 leukemia (Oatis et al., J. Med. Chem., 20: 1393 (1977)). 5,10-Dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin, and the corresponding 5,10-dideazafolic acid derivatives are reported by Taylor et al., J. Med. Chem., 28, No. 7: 914 (1985).
Additional derivatives of folic acid and aminopterin include: 10-oxafolic acid and 7,8-dihydro-10-oxafolic acid which are not effective inhibitors of DCM resistant Lactobacillus casei dihydrofolate reductase; 10-oxaaminopterin and 7,8-dihydro-10-thiofolic acid, which are potent DHFR inhibitors (Nair et al., J. Med. Chem., 19, NO. 6:825 (1976)); 10-thiafolic acid, a moderate DHFR inhibitor; and a very potent dihydrofolate reductase inhibitor, 10-thiaaminopterin (Kim et al., J. Med. Chem., 18, No. 8:776 (1975)).
This invention provides novel folic acid derivatives, their composition and use. In particular, this invention concerns 5-deaza-10-oxo- and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acid, intermediates for their preparation, pharmaceutical formulations containing the named compounds, and their use for the treatment of susceptible neoplasms.